Mild Inflammation Accelerates Colon Carcinogenesis in <i>Mlh1</i>-Deficient Mice

Abstract

Objective: Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. Method: Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1^–/–), Mlh1 heterozygous (Mlh1^+/–) and wild-type (Mlh1^+/+) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, β-catenin and p53. Results: Male and female Mlh1^–/– mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1^+/– and Mlh1^+/+ mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of β-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis. Conclusion: Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.

Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

“…In addition, we did not find histological signs for chronic inflammation in our cases. Evidence from mouse models, however, suggests that inflammation also contributes to CRC development after RT or alkylating agents 38 39. In a mouse model of chronic inflammation simulating inflammatory bowel disease, a higher frequency of MSI has been reported with a possible relation to base excision repair 40.…”

Apurinic/apyrimidinic endonuclease 1, the sensitive marker for DNA deterioration in dextran sulfate sodium-induced acute colitis

“…MMR contributes to the development of both sporadic and mucosal-damage-related neoplasia. 8,[12][13][14][15][16][17][18] We were interested in the relationship between MMR and BER in preventing DNA damage against DSS-induced colitis in young rats because MYH, which is involved in BER, is also associated with the development of colorectal cancer, and its activity is modulated by MMR and APE1. 20,21 We found that APE1 and MSH2 levels increased significantly at DSS-3d and DSS-5d, respectively.…”

“…[3][4][5][6] The information available regarding the molecular and genetic pathways that result in colorectal cancer, such as tumor suppressor genes, DNA mismatch repair (MMR) genes and proto-oncogenes, has increased markedly. The specific contributing mutations in genes such as adenomatous polyposis coli (APC) [7][8][9][10][11] and MMR 8, [12][13][14][15][16][17][18] have been investigated intensively. Mutations or deficiencies in APC and MMR contribute significantly to the development of age-related or familial colonic neoplasia and sporadic or mucosal damage-related neoplasia, respectively.…”

Inflammasomes in Inflammation-Induced Cancer

“…Mlh1 knockout mice displayed higher proportion of colon cancer after the administration of DSS. In colon cancerous tissues, the level of p53 and iNOS was increased and more oxidative DNA damage accumulated (92). …”